The present invention relates to a method for correcting a deficiency or distortion in the plasma melatonin level and profile in a human subject and to a pharmaceutical controlled-release formulation which comprises melatonin.
Melatonin is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident, regardless of whether the mammals are nocturnal or diurnal, and conversely, melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod and physiological processes, e.g. in animals which use changes in the photoperiod to time their thermoregulation, temporal signals to the thermoregulatory system are controlled by the daily rhythm in the duration of melatonin during the dark phase. Numerous studies have shown that melatonin has a potent influence on gonadal activity.
The timing of melatonin administration has been shown to be crucial for its biological activities. E.g., while in the case of rats whose circadian rhythms are disrupted or arrhythmic in constant light, as well as in the case of rats free running in constant darkness, their rhythms are synchronized by daily melatonin injections, by contrast it has been found that continuous availability of melatonin in circulation, of injection of melatonin in the morning, sometimes prevents gonodal responses to melatonin in the afternoon. The inventor has shown, e.g. in Zisapel et al, Neuroendocrinology 40: 102 (1985), that the inhibition by melatonin of the stimulated release of dopamine from rat hypothalamus, was highest in the early photophase and lowest in the early afternoon.
The ability of the animals or humans to respond to the melatonin signal may depend upon melatonin receptors. Thus, it has been shown that in Syrian hamsters, under a daily schedule of 14 hours light/10 hours darkness, the densities of melatonin binding sites in discrete brain areas (hypothalamus, medulla-pons and hippocampus) vary significantly over the 24-hour period with different patterns and phases, but no such variation was observed in other brain areas (striatum, parietal cortex, cerebellum). Only a partial overlap existed between the timing of peaks or troughs of melatonin binding sites and crests or nadirs in tissue melatonin content, so that the rhythms in melatonin binding sites may not be due to autoregulation of the receptors by the endogenous hormone. In this connection, it has also been shown that injection of exogenous melatonin to young rats or hamsters in the morning or late afternoon did not affect the density or diurnal variations in melatonin binding sites in most brain areas; in the hippocampus and midbrain, melatonin injected in the morning prevented the usual late afternoon rise in melatonin binding sites, whereas melatonin injected in the late afternoon suppressed the nocturnal rise in melatonin binding sites in the midbrain only.
It is also known that exogenously administered melatonin when administered in the late afternoon elicits antigonadal responses and decreases serum concentrations of testosterone in hamsters and immature rats, whereas in pinealectomized hamsters held in long days, the duration of melatonin administration is crucial in that 10 h infusions long days elicit gonadal regression in hamsters while after previous exposures to short days, 4-6 hour infusions of melatonin stimulated the gonads.
It is further known that in several species, including rats and humans, night-time melatonin production in the pineal gland declines with age. Moreover, a decline in 24 hour mean values and loss of circadian variations in melatonin binding sites was found to occur in discrete areas of the aged rat brain, as indicated by use of .sup.125 I-melatonin as a probe (Laudon et al, Neuroendocrinology, 48: 577, 1988). While the melatonin rhythm might not be the cause for the .sup.125 I-melatonin binding rhythms recorded in the rat brain, the possibility exists that the decline in amplitude of the melatonin rhythm leads to the dispersal of phase, resulting in the obliteration of rhythmicity in melatonin binding sites in the brain. In other words, the age-related decrease in melatonin levels and binding site density may lead to a decline in the ability of the neupoendocrine system to respond to photoperiodic messages.
U.S. Pat. No. 4,600,723 discloses the administration of melatonin in order to alleviate of prevent the negative effects of disturbances in circadian rhythms of bodily performance and function, such as may occur in a change of work patterns from day to night shift, or in cases of jet lag. Although conventional oral administration is exemplified, there is mentioned the possibility of administering melatonin a slow release form to maintain high plasma levels for the whole sleep period.
U.S. Pat. No. 4,654,361 discloses the administration of melatonin order to lower intraocular pressure in a human, where such pressure is abnormally high. Conventional oral and topical routes of administration are mentioned.
U.S. Pat. No. 4,945,103 discloses a method of treating premenstrual syndrome by administering melatonin at dosage levels sufficient to alleviate the symptoms. The melatonin may be administered orally or parenterally, or in the form of an implant or suppository which will provide a sustained release of melatonin Over time.
PCT Patent Application No. W0 88/07370 discloses the administration of melatonin for the purpose of inhibiting ovulation in human females, thereby effecting contraception, as well as for preventing breast cancer in women. The melatonin may be administered orally or parenterally, or in the form of an implant providing a sustained release of melatonin over time.
PCT Patent Application No. W0 89/04659 discloses the use of melatonin or related compounds, as a component in pharmaceutical compositions in order to counteract the effects of aging.
European Patent Application No. 0330625A2 discloses the production of melatonin and analogs thereof, as well as the use of melatonin administered orally. intramuscularly or endovenously for various therapeutic purposes. Also disclosed is the administration of melatonin in combination with an azidothymidine for the treatment of AIDS.
The entire contents of U.S. Pat. No. 4,600,723, U.S. Pat. No. 4,654,361, U.S. Pat. No. 4,945,103, PCT Patent Application No. W0 88/07370, PCT Patent Application No. WO 89/04659 and European Patent Application No. 0330625A2 are explicitly incorporated herein by reference.
Neither the scientific literature on the subject of melatonin, nor any of the above-mentioned Patents or published Patent Applications disclose or suggest the possibility or the desirability of either formulating or administering melatonin, so that it is released in the human body in a melatonin-deficient subject, in simulation of the profile in plasma of a human having a normal endogenous melatonin plasma profile.